1. Field of the Invention
This invention relates to powdered pharmaceutical compositions that exhibit improved stability of dispersibility over time for inhalation therapy, to processes for preparing such compositions, and to methods for treating certain disease states using such compositions. The invention is based on the discovery that the dispersibility of a powdered pharmaceutical composition can be maintained over time if the composition is prepared in a glassy state. While it has been known that the chemical stability of a pharmaceutical may be maintained in the glassy state, this is the first recognition that a glassy state composition may be used to maintain dispersibility of a powdered composition over time.
2. Background of the Invention
Over the years, certain drugs have been sold in compositions suitable for forming a drug dispersion for oral inhalation and consequent pulmonary absorption to treat various conditions in humans. Such pulmonary drug delivery compositions are designed to be delivered by inhalation of a drug dispersion by the patient so that the active drug within the dispersion can reach the lung. It has been found that certain drugs delivered to the lung are readily absorbed through the alveolar region directly into blood circulation. Thus, pulmonary delivery can be effective both for systemic delivery to treat various diseases and for localized delivery to treat diseases of the lungs.
Several approaches are used to deliver drugs via pulmonary absorption. These include liquid nebulizers, propellant-based metered dose inhalers (MDI""s), and breath-actuated or air-assisted dry powder inhalers (DPI""s). Aerosol dry powder inhalers provide a particularly promising approach for pulmonary delivery of drugs. DPI""s usually contain the powdered drug in a desiccated reservoir or blister pack. Inhaled or compressed air disperses the powder out of the device either directly into the patient""s mouth (breath-actuated DPI) or into a holding chamber (air assisted DPI). (See e.g. U.S. patent application Ser. No. 08/423,568, filed Apr. 14, 1995, which is incorporated herein by reference). Propellant based MDIs may also employ a dry powdered drug which is suspended in a liquified gas propellant. To deliver the drug, the pressurized gas is abruptly released through a valve and in the resulting spray, the propellant evaporates almost immediately leaving a fine dry powder. Aerosol powders are useful for the delivery of various pharmaceutical products including small molecules, such as steroids; peptides, such as hormone agonists; and proteins, such as insulin.
However, various disadvantages are evident with dry powder aerosol systems. If powder particles agglomerate to each other or adhere to the container or package walls over time, the concentration and thus the dosage of the delivered product will change. Furthermore, the powder particles may agglomerate and form hard cakes. With propellant systems, valve clogging may occur if the powder agglomerates or the powder concentration is too high. Additionally, powder may deposit on the valve seat and prevent the valve from closing properly. This leads to leakage of the propellant. Agglomeration also reduces the amount of drug that can be deposited in the lung, since particles typically must be below about 5 xcexcm for deposition in the respiratory bronchioles and below about 2 xcexcm for deposition through the alveolar ducts and alveoli. As an aerosol dry powder is stored on the shelf over a period of time, agglomeration may become more pronounced. The accumulation of moisture in particular can accelerate the rate of agglomeration. This degradation of the solid state of the formulation over time makes it difficult to ensure delivery of a consistent and accurate dose of the active drug during the shelf life of the aerosol product. With aerosol powders, shelf life is dependent on both the chemical stability of the active drug and the physical stability of the solid state delivery system. When the active drug has good chemical stability, product shelf life is dictated more by the physical stability of the dosage form. When the active is a labile compound, such as the protein xcex1-1 antitrypsin, the shelf life is dictated by both the chemical stability of the active drug in the dosage form and the physical stability of the dosage form itself. This has made the development of delivery systems for oral inhalation delivery of labile peptides and proteins particularly difficult. Additionally, since proteins and other macromolecules are poorly absorbed via other non-invasive routes of administration, pulmonary absorption is generally preferred.
The poor chemical stability of proteins in aqueous dosage forms is well known and solid dosage forms for proteins, i.e. dried proteins, are generally preferred. However, even in solid dosage forms, some proteins can be relatively unstable. This poor stability can be a product of both the method of preparing solid dosage forms, where the active drug is a protein, and of the storage environment around the protein within the dosage form.
A common method used to prepare relatively stable dry powders containing proteins is lyophilization (freeze-drying). However, lyophilization and further processing can force a protein to undergo significant chemical and physical changes. Processing events that may cause loss of activity include concentration of salts, precipitation, crystallization, chemical reactions, shear, pH, amount of residual moisture remaining after freeze-drying, and the like. Loss of activity is effected in part by physical changes to the tertiary structure of the protein, i.e. by unfolding.
Numerous solutions to the problem of protein stability in the dried form have been proposed in the literature. To optimize protein stability during lyophilization (process stability), for instance, the use of pH specific stabilizing ligands and non-specific stabilizing additives has been suggested. To stabilize the protein after lyophilization, it has been suggested that the excipients may form an amorphous glass with the protein. By supercooling a solution comprising a protein and excipients, freezing, wherein crystal habits can form, is bypassed and the solution forms a syrup followed by a viscoelastic rubber, and finally a glassy substance. The result is an amorphous solid, wherein the glassy excipient material, e.g. sucrose, is in an amorphous glassy form and encases the protein, thereby preventing any unfolding and slowing any molecular interactions or crossreactivity to a point of essential nonexistence, due to greatly reduced mobility of the protein and other molecules within the glassy composition. This process has been postulated to occur either via mechanical immobilization of the protein by the amorphous glass or via hydrogen bonding to polar and charged groups on the protein, i.e. via water replacement, thereby preventing drying induced denaturation and inhibiting further degrative interactions. As long as the glassy solid is stored at a temperature below its glass transition temperature and the residual moisture and, in some cases, oxygen remaining in the dried product is relatively low, the labile protein can remain relatively stable.
However, maintaining chemical and biological activity of the active protein is only half of the challenge where the delivery system comprises a dry powder aerosol dosage form. As previously discussed, the solid state stability of the dosage form itself must be maintained over the shelf-life of the product. That is, the dispersibility over time of the aerosol powder must be maintained. The importance of consistent physical stability of the aerosol powder dosage form is made evident by the need to accurately deliver relatively low doses of highly active proteins and peptides that are efficacious within very narrow therapeutic ranges. The high cost of many proteins and peptides also makes it critical to ensure that a substantial portion of available active drug dispersed within a dosage form is delivered to the pulmonary epithelia. Furthermore, for proteins, peptides, and small molecule pharmaceutical formulation for pulmonary delivery via oral inhalation, the U.S. Food and Drug Administration (FDA) requires that a given drug delivery system deliver the active drug at a concentration consistently within 85-115% of the labeled dose for the active, i.e. a delivered dose xc2x115% of the labeled dose. While the prior art has at least in part addressed the problems of chemical and physical stability of active protein drugs, it has not adequately addressed the issue of solid state stability of an aerosol dry powder, i.e. dispersibility, for delivering proteins. Nor has the prior art addressed the solid state stability of amorphous dry powder inhalable formulations for delivery of small molecule or peptide drugs.
Thus, there is a need for a means to deliver drugs via pulmonary absorption that ensures physical stability of the solid state dosage form over time. That is, there is a need for an aerosol dry powder dosage form or similar dosage form that has a stable dispersibility over time.
Objects of the Invention
It is an object of this invention to provide a pharmaceutical composition, particularly in a unit dosage form, for pulmonary administration that has stable dispersibility over time.
It is a further object of this invention to provide a process for manufacturing a pharmaceutical composition for pulmonary administration that has stable dispersibility over time.
A still further object of this invention is to provide a process for administering a pharmaceutical composition for pulmonary administration that has stable dispersibility over time.
A still further object of this invention is to provide a novel drug delivery system that is capable of maintaining a stable level of dispersibility over time.
One aspect of this invention is a powdered, dispersible composition having stable dispersibility over time, a characteristic glass transition temperature (Tg) and a recommended storage temperature (Ts), wherein the difference between Tg and Ts is at least about 10xc2x0 C. (i.e. Tgxe2x88x92Ts, is greater than 10xc2x0 C.), which composition comprises a mixture of a pharmaceutically-acceptable glassy matrix and at least one pharmacologically active material within the glassy matrix.
Another aspect of this invention is a powdered dispersible composition in unit dosage form having stable dispersibility over time and a characteristic glass transition temperature (Tg), in combination with labelling instructions for treating pulmonary or systemic disease in a mammalian subject that include a recommended storage temperature (Ts), wherein the difference between Tg and Ts is at least about 10xc2x0 C. The composition comprises a pharmaceutically acceptable glassy matrix and at least one pharmaceutically active material within the amorphous glassy matrix.
Still another aspect of this invention is a process for producing a powdered dispersible composition having stable dispersibility over time, a characteristic glass transition temperature (Tg) and a recommended storage temperature (Ts) wherein the difference between Tg and Ts is at least about 10xc2x0 C. The process comprises removing the solvent from a solution comprising a solvent, a glass former and a pharmacologically active material under conditions sufficient to form a glassy matrix having the pharmacologically active material within the matrix.